tbuckley/cabot-search huggingface dataset:
NIMG-109. A PILOT STUDY OF LYMPHOSCINTIGRAPHY WITH TRACER INJECTION IN THE HUMAN BRAIN
Authors: Andrew Coxon, Rupen Desai, Pujan Patel, Ananth Vellimana, Jon Willie, Joshua Dowling, Eric Leuthardt, Albert Kim, Tanner Johanns, Barry Siegel, Gavin Dunn
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Many groups have reported lymphatic and glymphatic structures in animal and human brains, but tracer injection into the human brain to demonstrate real-time lymphatic drainage and mapping has not been reported. Technetium (99mTc) tilmanocept is a radiopharmaceutical agent that binds CD206 and maps draining lymph nodes. We hypothesized that peritumoral 99mTc-tilmanocept injection into the brain parenchyma would map drainage to cervical lymph nodes. Here we show a paucity of tracer movement after injection due to a presumed inefficiency of glymphatic and lymphatic drainage. METHODS We enrolled 14 patients undergoing resection or stereotactic biopsy of suspected benign or malignant intracranial tumors. Patients received peritumoral injections of 99mTc-tilmanocept followed by planar or tomographic imaging. One patient was excluded from analysis because of tracer leakage during injection. RESULTS No patients showed drainage of 99mTc-tilmanocept to regional lymph nodes. On average, after correcting for radioactive decay, 70.1% (95% CI: 60.0%, 81.6%) of the tracer in the injection site and 78.1% (95% CI: 71.1%, 85.1%) in the whole-head on the day of surgery remained the morning after, with variable radioactivity in the subarachnoid space. The remaining fraction at the injection site was much larger than the expected fraction of 1.12% (95% CI: 1.07%, 1.17%) based on previously reported clearance rates from non-brain injections. We determined that this lack of drainage was not due to sequestration by a large population of CD206+ cells via immunohistochemistry of peritumoral tissue sections. Patients with benign or malignant tumors and a patient who underwent or minimally invasive stereotactic biopsy all showed no drainage. DISCUSSION In this pilot study, the lymphatic tracer 99mTc-tilmanocept was injected into the brain parenchyma, and there was an absence of drainage to the cervical lymph nodes. Our work demonstrates an inefficiency of drainage from the brain parenchyma and highlights an opportunity to improve brain immunosurveillance.
TMIC-22. INTERPLAY BETWEEN GBM AND IMMUNE CELLS IN THE MOUSE GLIOMA MICROENVIRONMENT AT SINGLE-CELL RESOLUTION
Authors: Anna Lenkiewicz, Karol Jacek, Mitrajit Ghosh, Salwador Cyranowski, Paulina Pilanc, Paulina Szadkowska, Natalia Ochocka, Bozena Kaminska
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most common primary tumor of the central nervous system in adults. GBM patients have a particularly poor prognosis and extremely short survival time due to lack of effective therapies and rapid tumor relapse. Neoplastic cells should be effectively recognized and destroyed by the immune system, but its antitumor activity is often inhibited by tumor-secreted factors that contribute to the tumor immunosuppressive microenvironment (TME). As TME plays a key role in cancer progression and immune evasion, understanding the interplay between GBM cells and myeloid and lymphoid populations is pivotal in creating new therapeutic strategies for GBM patients. To identify subtypes and functional diversity of immune cells in glioma TME we employed single-cell RNA and protein sequencing (CITEseq, Cellular Indexing of Transcriptomes and Epitopes by Sequencing) and Visium (10XGenomics) spatial transcriptomics. We characterized the populations of myelo- and lymphoid cells, and examined their unique transcription profiles, functional diversity and localization in TME. By combining analysis of CITE-seq with spatial transcriptomics we characterized and described 35 phenotypes of immune cells, which then we localized spatially within TME in GL261 mouse gliomas. Our results indicated that the peripheral monocytes/macrophages (Cd49d) localized in the tumor core, while microglia (Tmem119) accumulated at the invasive edge. Moreover, we observed a ring of activated astrocytes and rare T lymphocytes dispersed around the tumor. Finally, Ligand-Receptor and CellChat analysis of our CITE-seq results revealed the interplay between GBM, myeloid cells and lymphocytes, indicated on potential factors responsible for accumulation and tumor-evoked reprograming of immune cells. Single-cell technologies provide high-resolution insights into cellular and functional heterogeneity of gliomas, the analysis of which, in the future, will provide us with new therapeutic strategies for GBM patients. Studies were supported by NSC grant 2020/39/B/NZ4/02683 (BK) and PACIFIC Call 1 PAS (MG).
QOL-15. VALIDITY AND RELIABILITY EVALUATION OF PRO-CTCAETM FOR ADULT DIFFUSE GLIOMAS PATIENT IN CHINESE POPULATION. (VERONICA): A PRELIMINARY DELPHI STUDY
Authors: Chen Luo, Shuai Wu, Linbo Cai, Juxiang Chen, Song Chen, Zhou Fei, Lin Kong, Sanzhong Li, Hui Ma, Yonggao Mou, Xiaoguang Qiu, Kai Shu, Sida Song, Chongran Sun, Zhiwei Tang, Zanyi Wu, Zhang Xiong, Geng Xu, Jiankun Xu, Yongping You, Jianmin Zhang, Wei Zhang, Chunlong Zhong, Yourui Zou, Zhenyu Wu, Jinsong Wu
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVES Given the increasing importance of patient’s perspective in adverse events reporting, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™) has been proposed as new PRO measures in oncology; however, its implementation has not yet been evaluated in glioma patients, and standardized selection process of priority symptom terms has not been applied. METHODS A total of 16 experts (13 neurosurgeons, 2 radiotherapists, 1 psychiatrist) from 14 medical centers in China were invited to participate in a consensus-seeking 2-round online Delphi survey. Participants rated the level of their agreement with each symptom term likely to occur during adult diffuse gliomas treatment on a 5-point Likert scale. Terms not reaching consensus over the first round were modified in the second rounds. Consensus was defined as content validity index (CVI) &amp;gt; 0.78，coefficient of variation (CV)&amp;lt; 0.35 and average Likert score &amp;gt; 3.00. RESULTS Experts reached a consensus on 21 PRO-CTCAE™ symptom terms in the first Delphi round, and 10 terms in the second round. Likert scale scoring among all experts showed significant consistency (Round 1: Kendall’s W= 0.415，p＜0.001; Round 2: Kendall’s W = 0.351，P＜0.001). The 31 terms (38.75%) screened out of all 78 terms covered neurological symptoms(n=7), psychiatric symptoms(n=6), dermatological symptoms(n=6), gastrointestinal symptoms(n=5) and other common postoperative systemic symptoms of glioma patients. CONCLUSIONS We identified a customized PRO-CTCAE™ questionnaire containing a core set of priority symptom terms for the adult diffuse glioma through a 2-round Delphi survey. Next, a prospective, multi-center, real-word study would be performed to assess the validity, reliability and responsiveness of the customized PRO-CTCAE™ for adult diffuse glioma patients in Chinese population (VERONICA).
EXTH-38. NEOADJUVANT PD1 BLOCKADE ALTERS THE TUMOR IMMUNE MICROENVIRONMENT AFTER SURGERY IN A PRECLINICAL MODEL OF RECURRENT GLIOBLASTOMA
Authors: Lan Hoang-Minh, Kelena Klippel, Bently Doonan, Christina Von Roemeling, Vrunda Trivedi, Changlin Yang, Akshayaa Sriharan, Connor Francis, David Shin, Aida Karachi, Zhanna Galochkina, Matthew Sarkisian
Journal: Neuro-Oncology (2022)

Abstract SIGNIFICANCE Promising clinical trials for glioblastoma are evaluating the efficacy of neoadjuvant immunotherapy in the context of recurrent tumor surgery. OBJECTIVE We investigated the effects of neoadjuvant PD1 blockade on the glioma tumor microenvironment after surgery in a clinically relevant murine model of recurrent tumor. RESULTS Using a mouse resection model of KR158 glioblastoma that we established, we show that neoadjuvant PD1 inhibition and surgery enhance mouse survival and enhance the recruitment of CD8+ and CD4+ T cells at recurrent tumor sites following bulk tumor resection when compared with surgery followed by adjuvant immunotherapy. Transcriptome and spatial genomic analyses reveal alterations in immune exhaustion and activation pathway signaling genes after neoadjuvant anti-PD1 treatment when compared with adjuvant anti-PD1-treatment or surgery alone. CONCLUSIONS These studies provide insights into the effects of neoadjuvant PD1 blockade on the tumor microenvironment after surgery and uncover additional treatment targets that could be used in combination with this neoadjuvant therapy.
NCOG-12. IMPACT OF TUMOR-RELATED SEIZURES ON MENTAL HEALTH DISORDER ORDER IN LOW-GRADE GLIOMA
Authors: Debarati Bhanja, Djibril Ba, Kyle Tuohy, Hannah Wilding, Mara Trifoi, Varun Padmanaban, Guodong Liu, Michael Sughrue, Brad Zacharia, Douglas Leslie, Alireza Mansouri
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Majority of LGG patients experience seizures during their disease course, requiring anti-epileptic drugs (AEDs). Frequent seizures negatively impact health-related quality of life (HRQoL). AEDs, moreover, are hypothesized to have mood-modulating effects. As survival for LGG patients has been improving, it is essential that the impact of seizure burden and AEDs on mental health disorders (MHD) be considered. The objective was to measure an association of tumor-related seizures with MHD onset among LGG patients. METHODS This retrospective cohort study queried data from the IBM Watson Health MarketScan® Claims and Encounters Database (2005-2014) to identify LGG patients without prior MHD history who experienced glioma-related seizures. Presence of seizures was determined by anti-epileptic drug fills within one year following LGG diagnosis. Patients with new onset of MHDs were identified using ICD-9 codes for MHDs and psychotropic drug fills in the 12 months post-LGG diagnosis period. Unadjusted odds ratios measured associations between seizures and MHD prevalence. RESULTS 11,458 LGG patients with no history of MHD were included; 1,799 (15.7%) experienced seizures within 12 months of LGG diagnosis. Among them, 494 (27.5%) developed MHD in the post-LGG diagnosis period. Patients who experienced seizures were more likely to develop an MHD compared to patients who did not (OR, 2.19, 95% CI, 1.95–2.47). MHD incidence was significantly associated with female gender (OR, 1.14, 95%, 1.03–1.26) and age range of 35–44 (OR, 1.20, 95%, 1.03–1.39) compared to 18–34. CONCLUSION These findings demonstrated that tumor-related seizures were associated with MHD onset. This highlights the burden of seizures and regular AED use on mental health. The psychosocial and neurological aspects related to seizures and AEDs likely contribute to the multifaceted mental health disorder onset seen among these LGG patients. Proactive counseling, diagnosis, and management of MHDs in LGGs, particularly those with seizures, is warranted.
NIMG-49. RADIO-PATHOMIC MAPS OF DE-NOVO GLIOBLASTOMA IDENTIFY PHENOTYPES OF TUMOR INVASION ASSOCIATED WITH PROGNOSIS
Authors: Samuel Bobholz, Allison Lowman, Savannah Duenweg, Aleksandra Winiarz, Fitzgerald Kyereme, Elizabeth Cochran, Jennifer Connelly, Wade Mueller, Mohit Agarwal, Anjishnu Banerjee, Peter LaViolette
Journal: Neuro-Oncology (2022)

Abstract PURPOSE Although tumor is known to exist beyond the contrast-enhancing margin, a lack of access to pathological information beyond enhancement has hindered the study of non-angiogenic tumor characteristics and their effects on patient prognosis. This study tested the hypothesis that radio-pathomic maps of tumor characteristics developed using autopsy tissue samples can identify phenotypes relevant to patient survival and treatment outcomes. METHODS A dataset of autopsy tissue samples aligned to the MRI as ground truth from 65 glioma patients (training set n=43, test set n=22) was used to train machine learning models that predict and map tumor cellularity (Cell), extracellular fluid (ECF), and cytoplasm (Cyt) density following our previously published methodology (Bobholz et al. 2022). Cell, ECF, and Cyt maps were then generated from the pre-surgical MRI scans from an independent dataset of 80 glioblastoma patients. Each patient was separated into groups based on the appearance of tumor characteristics beyond the contrast-enhancing margin. Group phenotypes included Well-Circumscribed (WC) tumors with no tumor activity beyond contrast enhancement, Necrotic Front (NF) tumors with areas of necrosis extending beyond the tumor margin, Hypercellular Front (HF) tumors with areas of increased cellularity surrounding the tumor, and Hybrid Front (HYF) tumors with characteristics of both HF and NF tumors. A Cox regression was used to assess survival differences between phenotypes, controlling for treatment history. RESULTS Across the 80 patients, 22 were classified as WC, 14 were classified as HF, 24 were classified as NF, and 20 were classified as HYF. NF, HF, and HYF tumors each showed significant/trending reductions in survival when compared to WC tumors (HR=2.02, p=0.03; HR=2.0, p=0.06; and HR=1.75, p=0.09, respectively). CONCLUSION Radio-pathomic phenotypes identify characteristics beyond the contrast-enhancing margin that affect overall survival outcome in glioblastoma.
NCMP-20. NUMB CHIN SYNDROME: ATYPICAL PRESENTATION OF METASTATIC BREAST CANCER
Authors: Britta Bureau, Jennifer Connelly, Paul Barkhaus, Ryan Brennan
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVES 1. To report a variation of Numb Chin Syndrome (NCS) 2. Raise awareness and early localization of NCS to more efficiently develop a targeted treatment plan to prevent tumor spread and potentially improve clinical outcomes and survival. INTRODUCTION/BACKGROUND NCS is an uncommon but known complication of cancer. Prompt recognition is imperative to directed treatment. In some instances, numb chin may be complicated by other findings. CASE REPORT A 53-year-old female with past medical history of estrogen receptor positive invasive ductal breast carcinoma underwent partial mastectomy, chemotherapy, and radiation. After 6 years remission, new lung and liver metastases occurred, and chemotherapy resumed. Imaging was negative. Eight weeks later, she developed left chin numbness followed by progressive difficulty retaining food and drink. Her left lower lip weakened. Neurological examination revealed left lower lip weakness (showing a “droop” with attempted smile). The area of decreased sensation to sharp touch had expanded from the left chin to the nasolabial fold. The remainder of her neurological examination was unremarkable. Contrast-enhanced MRI was repeated which revealed a 1.9 cm enhancing left parotid mass. SUMMARY/ CONCLUSION NCS is defined as an ipsilateral loss of chin sensation. If there is no history of trauma or dental injury and especially if the presentation is atypical, then cancer is the most likely etiology. This case began as an uncomplicated NCS that rapidly expanded to involve a greater portion of the trigeminal nerve distribution, in addition to a branch of the facial nerve. Thus, each focal deficit was not the result of separate distal nerve lesions, but rather partial proximal cranial neuropathies at their parotid gland propinquity.
EXTH-05. TOWARD 100% CLINICAL EFFICACY FOR TUMOR-TREATING FIELDS
Authors: Kristen Carlson, Jack Tuszynski
Journal: Neuro-Oncology (2022)

Abstract In vitro and in animal models of various tumor cell types, empirical data suggest tumor-treating fields (TTFields) can attain 100% efficacy, with two pre-conditions: 1) Delivering sufficient electric field strength to the target tumor cells, and 2) Changing the direction of the imposed electric field such that intra-cellular structures at any angle with respect to the field see the required efficacious field strength. Requirement #2 reflects empirical findings as well as prevailing theories of TTFields’ mechanism of action, which center on mitosis disruption via energy imparted to polarizable intracellular structures aligned with the field. We tried various trial curve-fits to TTFields empirical dose-response curves. Quadratic formulae yield a close fit, resembling well-known radiotherapy linear-quadratic (LQ) curves and suggesting a connection between the mechanisms of the two treatment modalities: F98 (rat glioma): -16.3271x2 - 0.664019x+100 (R2=0.9995); MDA-MB-231 (human breast cancer): -9.64922x2 + 2.96348x + 100 (R2=0.9999); H1299 (human non-small cell lung carcinoma): -12.0515x2 - 1.58272x + 100 (R2=0.9993); B16 (mouse melanoma): -83.8066x2 + 47.4537x + 100 (R2=0.9954). We extrapolate these fits to predict the approximate required field strength seen at the target cells for 100% efficacy: F98: 2.45 V/cm; MDA-MB-231: 3.4 V/cm; H1299: 2.8 V/cm; B16: 1.4 V/cm. Alternatively, the LQ fits may not reflect the extrapolated high amplitude range for which data is lacking. Under two assumptions, 1) intracellular structures are randomly oriented in vivo, and 2) only two changes of TTFields direction are used, as is the current clinical practice, then extrapolating the dose-response curves predicts that infinite field strength is required for 100% efficacy, since some intracellular structures must be oriented at 90 degrees to the imposed field and the cosine of 90 degrees is zero. Adding a third TTFields direction, not necessarily orthogonal to the plane of the other two directions, can solve this problem.
RADT-23. MODALITY-SPECIFIC CNS INJURY FOLLOWING PROTON VS PHOTON BEAM RADIOTHERAPY IN GLIOMA
Authors: Sebastian Winter, Melissa Gardner, Michael Parsons, Clemens Grassberger, Marc Bussière, Felix Ehret, David Kaul, Wolfgang Boehmerle, Matthias Endres, Helen Shih, Jorg Dietrich
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND CNS injury following brain-directed radiotherapy (RT) is common and may mimic disease progression. Dosimetric advantages of protons (PRT) over photons (XRT) minimize radiation to healthy brain, potentially limiting radiotoxic sequelae. We characterized CNS radiotoxicity i.e., radiation-induced leukoencephalopathy (RIL), brain tissue necrosis (TN), and cerebral microbleeds (CMB), during progression-free survival (PFS) periods in glioma patients irradiated with PRT or XRT. METHODS 34 patients (19 male; mean age = 40.10y) with grade 2/3 gliomas treated by partial cranial RT were stratified by RT modality [XRT(n = 17) vs PRT(n = 17)] and matched on 11 criteria [age, sex, tumor type/location/laterality, mutational status (IDH; 1p19q deletion), concurrent/adjuvant chemotherapy, radiation dose/fractions] for retrospective analysis. Radiotoxicity was characterized longitudinally until 3 years post-RT via analysis of serial MRI T2/FLAIR- (RIL), T1+Contrast- (TN), and Susceptibility (CMB)-weighted sequences. RIL was rated using a novel scoring system with embedded Fazekas scale (intraclass correlation coefficient &amp;gt; 0.9), at global (whole-brain) and hemispheric levels. RESULTS Analysis of delayed radiotoxicity at 3 years post-RT identified significant modality-specific differences. While both groups developed moderate-to-severe RIL [62% (XRT) and 72% (PRT)], XRT resulted in greater RIL injury dynamics (i.e., average % change between 1 and 3 years post-RT) in the contralesional hemisphere [F(1, 31) = 4.32, p &amp;lt; .05]. Conversely, PRT was associated with higher TN incidence [6%(XRT) vs 18%(PRT) z = - 2.22, p &amp;lt; 0.03, two-tailed]. Finally, while CMB incidence [76%(XRT) vs 71%(PRT)] and burden [mean #CMB: 4.3(XRT) vs 4.2(PRT)] were comparable, lesion-to-radiation field (RF)-correlation identified preferential CMB clustering at RF margins with PRT [X2(2, N =200)= 8.8, p &amp;lt; .02]. CONCLUSIONS CNS radiotoxicity is common and progressive in glioma patients. Injury patterns suggest radiation modality specificity as RIL, TN, and CMB exhibit unique spatiotemporal differences following XRT vs PRT, likely reflecting dosimetric and biological differences between protons and photons. The impact of such sequelae on cognition is subject of current investigation.
STEM-02. GENERATION AND CHARACTERISATION OF A LIVING BIOBANK OF POST-SURGICAL RESIDUAL GLIOBLASTOMA TO IDENTIFY NOVEL THERAPEUTIC TARGETS
Authors: Connor McGarrity - Cottrell, Katie Myers, Dennis Wang, Mark Dunning, Veejay Bagga, Yahia Al-Tamimi, Saurabh Sinha, Ola Rominiyi, Spencer Collis
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma is the most common cancer arising within the brain and contributes to ~190,000 brain tumour related deaths/year globally. Current standard-of-care therapy consists of maximal safe surgical resection, radiotherapy with concomitant then adjuvant chemotherapy (Temozolomide) which triggers the cellular DNA damage response (DDR). However, survival for patients remains poor (median OS ~ 12-15 months). Lack of progress in the development and clinical translation of novel therapeutics is largely attributed to extensive inter- and intra-tumoral heterogeneity and resistant glioma stem cell (GSC) niches. Traditionally, primary ex vivo and in vivo models of glioblastoma have been derived from the resected tumour mass potentially omitting significant genetic, epigenetic and phenotypical characteristics exhibited by post-surgical residual tumour cells that are ultimately responsible for disease recurrence and morbidity. We therefore hypothesise that GSC’s isolated from the invasive edge of the tumour are inherently treatment resistant due to an increased “stemness” and upregulated DDR. Here we display novel methodology for the generation of multiple parallel primary ex vivo GSC cell models from anatomically discrete regions of specific partial lobectomy specimens. Importantly, these samples contain large portions of infiltrated adjacent brain to recapitulate features of resected (tumour core) and typically residual glioblastoma (distal invasive tumour edge). Initial RNA-seq analysis has revealed large divergent transcriptional landscapes of resected vs residual tumour cells and protein expression analyses has identified key differences in DDR proteins and subsequent cellular responses to current standard-of-care radio-chemotherapy regimens. Immunofluorescence analysis of DNA damage markers has also revealed differential capacity &amp; kinetics for repair of DNA damage between resected and residual GSC populations. These data therefore highlight the potential clinical relevance of our novel parallel resected and residual ex vivo glioblastoma models, which will hopefully aid evaluation of novel therapeutics capable of targeting post-surgical GSC subpopulations leading to improved disease outcomes.